This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic: 06-AR-103, Systems Biology for Skin and Rheumatic Diseases. Psoriasis (PS) is a complex inflammatory skin disease where genetic risk factors and environmental trigger contribute to the "rewiring" of the circuitry of the transcriptome of the skin. Until now an understanding of its systems biology of psoriasis were limited by genomic tools that were neither cost effective, nor comprehensive. PS affects as many as 7.5 million Americans (2-3% of the population) and between 10 and 30 percent of PS patients develop psoriatic arthritis (PsA). Both PS and PsA are serious conditions for which there are no cures, and warranting sophisticated medical care and therapies. Total direct and indirect health care costs of PS patients are ~ $11.25 billion annually. PS can cause as much disability as other major diseases, including diabetes, heart disease, hypertension and depression accompanied by thoughts of suicide. It goes hand-in-hand with myriad co-morbid conditions such as Crohn's disease, diabetes, metabolic syndrome, obesity, hypertension, heart attack, cardiovascular disease and liver disease. Despite progress in understanding altered cellular pathways and genetic risk factors of PS, it is still poorly understood. Current treatments present a challenge for patients and their health care providers because no one treatment works for everyone, some treatments lose effectiveness over time, many treatments used are in combination with other treatments, and all treatments may cause a unique set of side effects. With the development of high throughput Next-Generation DNA sequencing we are proposing to identify altered mRNAs, and small noncoding RNAs (including microRNAs) and model the altered networks of this disease. These data will also be a rich resource of deep sequence profiling data that will facilitate research by the psoriasis community. Moreover, altered networks of this disease may pave the way for targeted therapeutic intervention. This is a collaborative proposal from investigators who have pioneered the analysis of the psoriasis transcriptome, the development of tools for the analysis of expression and microRNA sequence datasets, and network building. The high throughput, and technological prowess of the genome sequencing center at Washington University school of medicine and the development of methods for massively parallel genome sequencing are technologies enabling the work described in this proposal. Our multidisciplinary collaborative group has proven expertise both in sample and library preparation methods, Next-Generation sequencing methods and computational analysis to complete the aims of this proposal in a two year time-period. Psoriasis is an inflammatory disease of the skin for which there is no cure. It affects many individuals worldwide, and 2-3% of Americans. The expected outcome of this study is the identification of novel networks and cellular factors in psoriasis (PS) that can be targeted for the development of novel treatments. )